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Published on: August 25, 2021
Strain-specific spontaneous and NNK-mediated tumorigenesis in Pten+/- mice
Mary Christine Hollander1, Andria R Balogh, Jaminelli Liwanag
1Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20889, USA.
Abstract:
Pten is a negative regulator of the Akt pathway, and its inactivation is believed to be an etiological factor in many tumor types. Pten+/- mice are susceptible to a variety of spontaneous tumor types, depending on strain background. Pten+/- mice, in lung tumor-sensitive and -resistant background strains, were treated with a tobacco carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), to determine whether allelic Pten deletion can cooperate with NNK in carcinogenesis in lung or other tissues. In lung tumor-resistant C57BL/6 Pten+/- or +/+ mice, NNK treatment did not lead to any lung tumors and did not increase the incidence or severity of tumors previously reported for this strain. In contrast, in a lung tumor-susceptible pseudo-A/J strain, there was a dose-dependent increase in lung tumor size in Pten+/- compared with +/+ mice, although there was no increase in multiplicity. No other tumor types were observed in pseudo-A/J Pten+/- mice regardless of NNK treatment. Lung tumors from these Pten+/- mice had K-ras mutations, retained Pten expression and had similar Akt pathway activation as lung tumors from +/+ mice. Therefore, deletion of a single copy of Pten does not substantially add to the lung tumor phenotype conferred by mutation of K-ras by NNK, and there is likely no selective advantage for loss of the second Pten allele in lung tumor initiation.
Insights
Allelic deletion of the Pten gene did not significantly enhance lung tumor development in mice treated with the carcinogen NNK. Loss of one Pten copy did not provide a selective advantage for lung tumor initiation.
Area of Science:
- Oncology
- Genetics
- Carcinogenesis
Background:
- The phosphatase and tensin homolog (Pten) gene acts as a tumor suppressor by negatively regulating the Akt signaling pathway.
- Inactivation of Pten is implicated in the development of various cancers.
- Pten+/- mice exhibit susceptibility to spontaneous tumors, influenced by genetic background.
Purpose of the Study:
- To investigate if heterozygous Pten deletion cooperates with NNK, a tobacco carcinogen, in promoting lung carcinogenesis.
- To assess the impact of allelic Pten loss on tumor development in both lung tumor-sensitive and -resistant mouse strains.
Main Methods:
- Pten+/- and Pten+/+ mice on C57BL/6 (resistant) and pseudo-A/J (sensitive) backgrounds were treated with NNK.
- Tumor incidence, multiplicity, and size were evaluated in various tissues, with a focus on the lungs.
- Molecular analysis of lung tumors included K-ras mutation status, Pten expression, and Akt pathway activation.
Main Results:
- In resistant C57BL/6 mice, NNK did not induce lung tumors or increase tumor incidence/severity in Pten+/- mice.
- In susceptible pseudo-A/J mice, NNK caused a dose-dependent increase in lung tumor size in Pten+/- mice but not multiplicity.
- Lung tumors in Pten+/- mice exhibited K-ras mutations and retained Pten expression, with similar Akt pathway activation as in Pten+/+ mice.
Conclusions:
- Loss of one Pten allele does not significantly exacerbate NNK-induced lung tumorigenesis.
- The study suggests no selective advantage for the loss of the second Pten allele during NNK-driven lung tumor initiation.
- Pten heterozygosity alone is insufficient to drive significant lung tumor development in the context of K-ras mutations induced by NNK.
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